Organic Synthesis of Biologically Interesting Compounds and Organosulfur/Selenium Chemistry

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Our work is in the area of synthetic organic chemistry, generally directed toward the synthesis of biologically interesting molecules, and frequently based on novel aspects of organosulfur and -selenium chemistry. Our program includes both the discovery of novel synthetically useful reactions and their application to specific target structures. Glutathione peroxidase (GPx) is a selenoenzyme that protects higher organisms from oxidative stress by catalytically destroying harmful peroxides, byproducts of aerobic metabolism that are implicated in inflammation, cardiovascular and neurological disease, mutagenesis and other deleterious conditions. GPx works in concert with the tripeptide thiol glutathione, which functions as a sacrificial reductant in this process. We are designing and synthesizing novel small-molecule selenium compounds with unusual structural motifs that mimic the activity of the enzyme and we are investigating the mechanisms by which they function. Our principal objective is to develop novel compounds that could protect heart attack and stroke victims from cardiovascular and neurological damage, which occurs during ischemic reperfusion (e.g. with clot-busting drugs). Future work will be directed toward the development of compounds with improved catalytic activity, greater water-solubility and slower clearance than demonstrated by several of our earlier compounds. In any redox process, for every reduction there is an accompanying oxidation. Thus, in different circumstances, our GPx mimetics could, in principle, be used to catalyze the oxidation of organic substrates with hydrogen peroxide, a cheap and environmentally benign oxidant. We have recently demonstrated that one of our GPx mimetics (a cyclic seleninate ester) can effectively catalyze several synthetically useful processes, often employed in the pharmaceutical and fine chemical manufacturing sectors. Our objective is to improve our mechanistic understanding, to expand the scope of these reactions as broadly as possible and to develop enantioselective variations of these processes. In another project, novel cyclization protocols based on unsaturated sulfones are being developed that provide efficient new routes to a variety of nitrogen heterocycles that comprise structural motifs common in alkaloids and synthetic medicinal compounds. For example, we recently discovered a Cu-catalyzed cross-coupling reaction that provides a new synthetic route to indoles, one of the most privileged classes of compounds in nature and medicine, from anilines and acetylenic sulfones. This process tolerates the presence of air and water, requires no ligands and employs stable Cu(II) salts instead of the more customary, but less air-stable Cu(I) species. Applications of these cyclizations to the synthesis of the structurally complex cylindricine marine alkaloids and to dendrobatid (poison frog) alkaloids, many of which have cardiotonic, analgesic and other useful activities, are being investigated. This work provides potential health and economic benefits to Canada: (1) Heart attacks and strokes create considerable suffering and are both a leading cause of death and an economic liability in developed countries. Our selenium-based antioxidants could reduce neurological and cardiovascular damage to such patients. (2) Development of novel selenium-based redox catalysts for oxidation processes of importance in both the laboratory and in industry could provide cheaper and more efficient alternatives. (3) Discovery of concise new synthetic methodology for preparing diverse nitrogen heterocycles that are core structures in many medicinal compounds under efficient, environmentally benign conditions could be advantageous to the pharmaceutical, biotech and fine chemical industries.